CHAPTER 7 LIPID METABOLISM

Lecture 1 Lipids and their functions Lecture 2 Lipid biosynthesis Lecture 3 Fats/ Triacylglycerols catabolism

Lecture 1 Lipids in and their functions Chapter 9

What are lipids? Lipids are a broad group of naturally-occurring molecules which includes fats, triacylglycerols, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K) , phospholipids, glycolipids, and others . Lipids molecules are rich in carbon and hydrogen but contain relatively few oxygen atoms. Lipids are insoluble in water.

Figure 9.1 Principles of Biochemistry, 5/e(© 2012 Moran & Horton) Structural relationships of the major classes of lipids. Figure 9.1 Principles of Biochemistry, 5/e(© 2012 Moran & Horton)

Fatty Acids The simplest lipids are fatty acids—these are long-chain hydrocarbons with a carboxylate group at one end.

Structures of three C18 fatty acids Figure 9.3 Principles of Biochemistry, 5/e(© 2012 Moran & Horton)

The existence of lipids  Peanut Rapeseed Sesame sunflower Soybean adipocytes or adipose cells【脂肪细胞 】. Plants：mainly in fruits and seeds . Fat accounts for approximately 40-50%

Animals：mainly in adipose tissue adipocytes or adipose cells【脂肪细胞 】.

The main biological functions of lipids Energy storage: The complete oxidation of fatty acids provides high caloric content, about 9 kcal/g, compared with 4 kcal/g for the breakdown of carbohydrates and proteins. Bears store an enormous amount of body fat in preparation for their long sleep.

The main biological functions of lipids cont’ Cell membrane structure The glycerophospholipids, are the main structural component of biological membranes, other non- glyceride lipid components such as sphingomyelin , and sterols, are also found in biological membranes . The glycerophospholipids 【甘油磷脂】, are the main structural component of biological membranes , other non-glyceride lipid components such as sphingomyelin 【神经鞘磷脂】, and sterols 【固醇类】, are also found in biological membranes .

The main biological functions of lipids cont’ Signals, cofactors, and pigments Some types of lipids, although present in relatively small quantities, play critical roles as cofactors or signals. Lipidic conjugated dienes serve as pigments in flowers and fruits and give bird feathers their striking colors.

The early 21st century has seen the development of a global epidemic of obesity, which is caused by a number of factors including willpower, lifestyle and genetics. Severe obesity can make you dead, it can make you sick, it can make you sad, it can make you alone, it can make you poor.

Lecture 2 Lipid biosynthesis

In animal tissues, triacylglycerols synthesized from two precursors (fatty acyl–CoA and L-glycerol 3-phosphate) and several biosynthetic steps. 直接原料: 3-磷酸甘油; 脂酰CoA

Glycerol 3-phosphate synthesis 3-磷酸甘油的合成:3-磷酸甘油醛,磷酸甘油脱氢酶,3-磷酸甘油,甘油甘油激酶

Biosynthesis of fatty acids Fatty acids are formed by the action of Fatty acid synthases from acetyl-CoA and malonyl-CoA precursors The formation of malonyl-CoA from acetyl-CoA is an irreversible process, catalyzed by acetyl-CoA carboxylase.

Fatty acid synthesis involve three stages Transport of acetyl-CoA into the cytosol Carboxylation of acetyl-CoA to form malonyl- CoA The elongation cycle of fatty acid synthesis 乙酰CoA的转运(由线粒体转运至细胞质）乙酰CoA的羧化：乙酰CoA →丙二酸单酰CoA 脂肪酸链的合成

Transport of acetyl-CoA into the cytosol In nonphotosynthetic eukaryotes, nearly all the acetyl-CoA used in fatty acid synthesis is formed in mitochondria from pyruvate oxidation and from the catabolism of the carbon skeletons of amino acids. The mitochondrial inner membrane is impermeable to acetyl-CoA, so an indirect shuttle transfers acetyl group equivalents across the inner membrane. 乙酰CoA的转运(柠檬酸穿梭系统)

Carboxylation of acetyl-CoA to form malonyl-CoA The formation of malonyl-CoA from acetyl-CoA is an irreversible process, catalyzed by acetyl-CoA carboxylase.

The elongation cycle of fatty acid synthesis In all organisms, the long carbon chains of fatty acids are assembled in a repeating four-step sequence, catalyzed by a system collectively referred to as fatty acid synthase. 脂肪酸链的合成（分为三阶段行）: 脂肪酸链的合成在脂肪酸合酶系统上分为三阶段行： ☆酰基的转移：乙酰基转移到中央巯基上,再转移到外围巯基上 ☆脂肪酸链的延伸：缩合，还原，脱水，还原 ☆ 脂酰基的水解：硫解酶

Acyl carrier protein (ACP) is the shuttle that holds the system together. The E.coli ACP is a small protein (Mr 8,860) containing the prosthetic group 4- phosphopantetheine.

Synthesis of malonyl ACP from malonyl CoA and acetyl ACP from acetyl CoA.

Step1: Condensation 【缩合反应】

Step2: Reduction

Step3: Dehydration

Step4: Reduction

The overall process of palmitate synthesis.

Fatty Acid Synthesis Occurs in the Cytosol of Many Organisms but in the Chloroplasts of Plants

Long-chain saturated fatty acids are synthesized from palmitate Fatty Acid Extension and Desaturation

Desaturation of Fatty Acids Requires a Mixed-Function Oxidase Oleic acid, 18:1（△9） Linoleic acid Linolenic acid 【油酸】【亚油酸】【亚麻酸】【花生四烯酸】 Arachidonic acid ,20（△5,8,11,14）

The double bond is introduced into the fatty acid chain by an oxidative reaction catalyzed by fatty acyl–CoA desaturase.

Lecture 3 Fats/ Triacylglycerols catabolism

The degradation of triacylglycerols Lipase triacylglycerols + 3H2O glycerol + 3 fatty acids

Glycerol metabolism Glycerol is converted to glyceraldehyde-3-P, and enters glycolysis or gluconeogenesis. 95% of energy of fat from fatty acids, 5% from glycerol.

Fatty acid oxidation Major pathway: -oxidation Minor pathway:    CH3-(CH2)n-CH2-CH2-COOH Major pathway: -oxidation Minor pathway: -oxidation -oxidation Oxidation of Unsaturated fatty acids Oxidation of odd-carbon fatty acids

β-Oxidation In 1904, Franz Knoop fed dogs labeled at their -carbon atoms of even-numbered- and odd-numbered FAs by a benzene ring and isolated the phenyl-containing metabolic products (glycine adduct) from their urine (phenylaceturic acid and hippuric acid ). FAs

苯乙酸 苯甲酸

β-oxidation is the process by which fatty acids, in the form of Acyl-CoA molecules, are broken down in mitochondria and/or in peroxisomes to generate Acetyl-CoA. 在一系列酶的作用下,脂肪酸的α,β碳原子上脱氢氧化并断裂,生成一分子乙酰CoA和少二个碳原子的脂酰CoA，通过上述氧化方式不断进行，脂肪酸最后被完全氧化生成乙酰CoA的过程。

The β- oxidation of fatty acids involve three stages Activation of fatty acids in the cytosol Transport of fatty acids into mitochondria β- oxidation proper in the mitochondrial matrix 脂肪酸的活化（细胞质中）脂酰CoA转运入线粒体线粒体基质中的β-氧化

Activation of fatty acids in the cytosol Acyl-CoA synthetases 2ATP lost ！ Fatty acids are linked to coenzyme A before they are oxidized

Transport of fatty acids into mitochondria need carnitine shuttle hitchhike

L-carnitine

The oxidation of saturated fatty acids has four basic steps Dehydrogenation Hydratation Thiolysis 在线粒体中，脂酰CoA每进行一次β-氧化要经过脱氢、加水、再脱氢 、硫解四步，生成一分子比原来少两个碳原子的脂酰CoA及一分子乙酰CoA。

Dehydrogenation Acyl-CoA dehydrogenase fatty Acyl-CoA Trans-∆2-Enoyl-CoA 【△ 2 -反烯脂酰CoA】

Hydratation enoyl-CoA hydratase trans-∆2-enoyl-CoA L-β-hydroxyacyl-CoA 【△2-反烯脂酰CoA】【L-β-羟脂酰CoA】

Dehydrogenation L-hydroxyacyl-CoA dehydrogenase β-ketoacyl-CoA derivative 【L-β-羟脂酰CoA】【 β-酮脂酰CoA 】.

Thiolysis Thiolase Thiolysis by a second CoA molecule to form Acetyl CoA and Acyl-CoA shortened by two carbon atoms, is catalyzed by β- ketothiolase.

Acetyl-CoA Activation Transportation Mitochondria membrane Mitochondrial matrix Dehydrogenation β-Oxidation Hydration Dehydrogenation Thiolysis Cytoplasmic Acetyl-CoA

The overall equation is:

The glyoxylate cycle The glyoxylate cycle is an anabolic metabolic pathway occurring in plants, and several microorganisms, such as E. coli and yeast. Germinating seeds can therefore convert the carbon of stored lipids into glucose. 【乙醛酸循环】 植物及某些微生物细胞内脂肪酸氧化分解为乙酰CoA之后，在乙醛酸体(glyoxysome)内生成琥珀酸、乙醛酸和苹果酸；此琥珀酸可用于糖的合成，该过程称为乙醛酸循环(glyoxylic acid cycle,GAC)。

Isocitrate lyase and malate synthase are unique to the glyoxylate cycle. Notice that two acetyl groups (pink) enter the cycle and four carbons leave as succinate (blue).

The net reaction for the GAC is as follows： 2CH3CO-SCOA+2H2O+NAD+ Succinate+2CoASH+NADH+H+

FIGURE 16–21 Electron micrograph of a germinating cucumber seed, showing a glyoxysome, mitochondria, and surrounding lipid bodies.

In germinating seeds, the enzymatic transformations of dicarboxylic and tricarboxylic acids occur in three intracellular compartments: mitochondria, glyoxysomes, and the cytosol. There is a continuous interchange of metabolites among these compartments.

The reactions of the glyoxylate cycle (in glyoxysomes) proceed simultaneously, and mesh with, those of the citric acid cycle (in mitochondria), as intermediates pass between these compartments.

Sugar Lipid Metabolism Lipids of oil plant seeds Acetyl-CoA Glyoxylate cycle Succinic acid + Oxaloacetate Gluconeogenesis Sugar

Coordinated regulation of glyoxylate and citric acid cycles. The partitioning of isocitrate between the citric acid cycle and the glyoxylate cycle is controlled at the level of isocitrate dehydrogenase, which is regulated by reversible phosphorylation.